This application is a 35 USC xc2xa7371 of PCT/JP00/0082 filed on Jan. 11, 2000, which in turn claims the benefit of Japanese Application No. 4384/1999 filed on Jan. 11, 1999.
The present invention relates to cinnamamide derivatives and pharmaceutical compositions containing them. In particular, the present invention relates to an immunomodulatory agent and/or a prophylactic or therapeutic agent for nephrotic syndrome, circulatory disorders or respiratory diseases.
Interleukin 12 (IL-12) is currently known to play an important role in the differentiation of CD4+ T lymphocytes into Th1 cells, and is also suggested to be a relevant to diseases associated with cellular immunity. Interleukin 6 (IL-6) is also known to induce cell growth of various cell types, as well as B cell growth and differentiation. On the contrary, Interleukin 10 (IL-10) is reported to have an inhibitory activity against cellular immunity. It is pointed out that IL-10 is relevant to diseases resulting from suppressed immunity. Accordingly, compounds which control the production of IL-6, IL-10 and IL-12 may be revolutionary new drugs that are expected to be effective in the treatment of diseases including autoimmune diseases resulting from excessive immunity (e.g., nephrotic syndrome, immunological rejection in transplantation, rheumatism, allergy), diabetes, liver disorders and tumors.
Since thromboxane A2, which is produced in platelets, the lungs and the like, has strong platelet aggregation and smooth muscle constrictor activities, the regulation of thromboxane A2 production influences blood pressure, bronchial asthma and/or blood coagulation. Accordingly, compounds which inhibit thromboxane A2 synthase may be revolutionary new drugs that are expected to be effective for circulatory disorders (e.g., ischemic heart disease, thromboembolic disorder, disorder of cerebral circulation) and respiratory diseases (e.g., asthma).
Steroids are used as a first-choice drug for the treatment of nephrotic syndrome, but there is a problem that steroids cause disturbances in growth because nephrotic syndrome is often found in children. Cyclosporine is used for the treatment of intractable nephrosis, but cyclosporine is required to be administered while monitoring its blood level because it causes renal disorders including decreased renal function and hypertension. Under these circumstances, it is also desirable to develop an effective and less toxic therapeutic agent for nephrotic syndrome in the medical aspect.
An object of the present invention is to provide novel cinnamamide derivatives and pharmaceutical compositions containing them, in particular, to provide an immunomodulatory agent and a prophylactic or therapeutic agent for nephrotic syndrome, circulatory disorders or respiratory diseases.
The present invention encompasses the following embodiments.
(1) A cinnamamide derivative having the following formula (I): 
wherein
R1 represents a hydroxyl group, a C1-6-alkoxy group, an arylalkoxy group or a substituted or unsubstituted amino group;
R2 and R3 are same or different, each of which represents a hydrogen atom, a halogen atom or a C1-4-alkyl group;
R4 represents a hydrogen atom or a C1-6-alkyl group;
R5 represents a hydrogen atom, a C1-6-alkyl group or an aryl group;
R6 represents a hydrogen atom, a C1-6-alkyl group, a cyano group or a C1-6-alkoxy-carbonyl group;
W represents an oxygen atom, a sulfur atom, an imino group, a methylene group, a hydroxymethylene group (xe2x80x94CH(OH)xe2x80x94) or a carbonyl group (xe2x80x94COxe2x80x94);
X and Y are same or different, each of which represents an oxygen atom or a sulfur atom;
m represents an integer of 0 to 2;
n represents an integer of 1 to 3; and
when m is 0, a group: xe2x80x94C(R2)(R3)xe2x80x94Wxe2x80x94 may represent a vinylene group (xe2x80x94CHxe2x95x90CHxe2x80x94);
or a pharmaceutically acceptable salt thereof.
(2) The cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) above, wherein the substituted amino group mentioned for R1 is substituted with one or two groups selected from a substituted or unsubstituted C1-6-alkyl group, a substituted or unsubstituted C3-6-cycloalkyl group, a substituted or unsubstituted C1-6-alkoxy group and a hydroxyl group; or is a cyclic amino group.
(3) A pharmaceutical composition, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(4) An immunomodulatory agent, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(5) A prophylactic or therapeutic agent for nephrotic syndrome, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(6) A prophylactic or therapeutic agent for circulatory disorders, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
(7) A prophylactic or therapeutic agent for respiratory diseases, which comprises as an active ingredient the cinnamamide derivative or pharmaceutically acceptable salt thereof according to (1) or (2) above.
In the above formula (I), a C1-6-alkoxy group mentioned for R1 includes a linear or branched C1-6-alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy and n-hexyloxy. An arylalkoxy group mentioned for R1 includes a C1-3-alkoxy group substituted with a substituted or unsubstituted aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), for example, benzyloxy and phenethyloxy.
An amino group mentioned for R1 may be substituted with at least one group selected from a substituted or unsubstituted C1-6-alkyl group, a substituted or unsubstituted C3-6-cycloalkyl group, a substituted or unsubstituted C1-6-alkoxy group and a hydroxyl group. This amino group may also be a cyclic amino group. A C1-6-alkyl group used as a substituent on the above amino group includes a linear or branched C1-6-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl and hexyl. Such a C1-6-alkyl group may further be substituted with at least one group selected from, for example, a C1-6-alkoxy group (e.g., methoxy, ethoxy), a heterocyclic group (e.g., pyridyl, furyl), an aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), an arylthio group (e.g., phenylthio, p-methoxyphenylthio, tolylthio, naphthylthio) and a C1-6-alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxy-carbonyl).
A C3-6-cycloalkyl group used as a substituent on the above amino group includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Such a C3-6-cycloalkyl group may further be substituted with at least one group selected from, for example, a C1-6-alkoxy group (e.g., methoxy, ethoxy), a heterocyclic group (e.g., pyridyl, furyl), an aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), an arylthio group (e.g., phenylthio, p-methoxyphenylthio, tolylthio, naphthylthio) and a C1-6-alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl).
A C1-6-alkoxy group used as a substituent on the above amino group includes a linear or branched C1-6-alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy and n-hexyloxy. Such a C1-6-alkoxy group may further be substituted with at least one group selected from, for example, a C1-6-alkoxy group (e.g., methoxy, ethoxy), a heterocyclic group (e.g., pyridyl, furyl), an aryl group (e.g., phenyl, p-methoxyphenyl, tolyl, naphthyl), an arylthio group (e.g., phenylthio, p-methoxyphenylthio, tolylthio, naphthylthio) and a C1-6-alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl).
An amino group substituted with a substituted or unsubstituted C1-6-alkyl group includes methylamino, ethylamino, n-propylamino, isopropylamino, n-hexylamino, dimethylamino, diethylamino, benzylamino, picolylamino, 2-methoxyethylamino, 2-phenylthioethylamino, and ethoxycarbonylmethylamino. An amino group substituted with a substituted or unsubstituted C3-6-cycloalkyl group includes cyclopentylamino and cyclohexylamino. An amino group substituted with a substituted or unsubstituted C1-6-alkoxy group includes methoxyamino. An amino group substituted with a hydroxyl group includes hydroxylamino. An amino group substituted with several substitutents includes N-methoxy-N-methylamino and N-hydroxy-N-methylamino. A cyclic amino group includes morpholino and piperidino.
In the above formula (I), a C1-4-alkyl group mentioned for R2 or R3 includes a linear or branched C1-6-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. A C1-6-alkyl group mentioned for R4, R5 or R6 includes a linear or branched C1-6-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl and hexyl.
A halogen atom mentioned for R2 or R3 includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
An aryl group mentioned for R5 includes phenyl, p-methoxyphenyl, tolyl and naphthyl.
A C1-6-alkoxy-carbonyl mentioned for R6 includes a carbonyl group substituted with a linear or branched C1-6-alkoxy group, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl and n-hexyloxycarbonyl.
In the above formula (I), a pyridyl group may be any one of 2-pyridyl, 3-pyridyl or 4-pyridyl.
In the present invention, a pharmaceutically acceptable salt may be an inorganic acid salt including hydrochloride, sulfate, hydrobromide, nitrate and phosphate, or an organic acid salt including trifluoroacetate, tartrate, citrate, malate, maleate, fumarate, methansulfonate, benzenesulfonate and toluenesulfonate. Some compounds may take the form of hydrates, which naturally fall within the scope of the present invention.
Compound (I) of the present invention also has cis- and trans-stereoisomers, as is apparent from its chemical structure. These stereoisomers naturally fall within the scope of the present invention.
Compound (I) of the present invention may be prepared by various methods. Representative methods (1) to (4) are presented below:
Method (1) Where W and Y are Oxygen Atoms in Formula (I):
Compound (I) of the present invention may be prepared by reacting a carboxylic acid of formula (II):
R7Oxe2x80x94Arxe2x80x94C(R5)xe2x95x90C(R6)xe2x80x94COOHxe2x80x83xe2x80x83(II)
wherein
R7Oxe2x80x94Ar represents a phenyl group which is substituted with a hydroxyl group having an easily removable protecting group R7; and
R5 and R6 are as defined above;
or reactive derivatives thereof, with an amine of formula (III):
R4xe2x80x94NHxe2x80x94(CH2)nxe2x80x94Pyxe2x80x83xe2x80x83(III)
wherein
Py represents a 2-pyridyl, 3-pyridyl or 4-pyridyl group; and
R4 and n are as defined above;
to give an amide derivative of formula (IV):
R7Oxe2x80x94Arxe2x80x94C(R5)xe2x95x90C(R6)xe2x80x94CON(R4)xe2x80x94(CH2)nxe2x80x94Pyxe2x80x83xe2x80x83(IV)
wherein
R4, R5, R6, R7Oxe2x80x94Ar, Py and n are as defined above;
and then removing the protecting group R7 from the hydroxyl group to provide a compound of formula (V):
HOxe2x80x94Arxe2x80x94C(R5)xe2x95x90C(R6)xe2x80x94CON(R4)xe2x80x94(CH2)nxe2x80x94Pyxe2x80x83xe2x80x83(V)
wherein
HOxe2x80x94Ar represents a phenyl group substituted with a hydroxyl group; and
R4, R5, R6, Py and n are as defined above;
followed by alkylation of compound (V) in the presence of a base using a halide of formula (VI): 
wherein
Hal represents a halogen atom such as a chlorine or bromine atom; and
R1, R2, R3, X and m are as defined above.
Method (2) Where Y is an Oxygen Atom in Formula (I):
Compound (I) may be prepared by reacting a carboxylic acid of formula (VII):
R1xe2x80x94C(xe2x95x90X)xe2x80x94(CH2)mxe2x80x94C(R2)(R3)xe2x80x94Wxe2x80x94Arxe2x80x94C(R5)xe2x95x90C(R6)xe2x80x94COOHxe2x80x83xe2x80x83(VII)
wherein
Ar represents a phenyl group; and
R1, R2, R3, R5, R6, m and W are as defined above;
or reactive derivatives thereof, with an amine of formula (III):
R4xe2x80x94NHxe2x80x94(CH2)nxe2x80x94Pyxe2x80x83xe2x80x83(III)
wherein
Py, R4 and n are as defined above.
Cinnamic acid derivatives (II) and (VII) and amine compound (III), which are used as starting materials, are commercially available or may be prepared in a general manner.
When compound (I) has a carbonyl group as group W, such a compound may be prepared by oxidizing a compound prepared from the above method (2), in which W is a hydroxymethylene group (xe2x80x94CH(OH)xe2x80x94), using manganese dioxide or pyridinium dichromate or by Swern oxidation.
When compound (II) or (VII) is provided in the form of carboxylic acid, in particular, these reactions are preferably carried out in the presence of a condensation agent such as dicyclohexylcarbodiimide, N,Nxe2x80x2-carbonyldiimidazole, 1-hydroxy-benzotriazole, N-hydroxysuccinimide, diethylphosphoryl cyanide, diphenylphosphoryl azide. It is particularly advantageous to use diethylphosphoryl cyanide in combination with triethylamine. Reactive derivatives of compound (II) or (VII) include acid halides, acid anhydrides, mixed acid anhydrides and the like.
These reactions are preferably carried out in an inert solvent, including organic solvents such as tetrahydrofuran, dimethylformamide and dichloromethane, in particular, under anhydrous conditions. The reactions may be carried out at any temperature, in general, under ice-cold conditions up to under ambient conditions. The reaction time is generally in the range of 0.5 to 20 hours. Following the reaction, the product of interest may be isolated in a general manner.
As a protecting group R7 for a hydroxyl group in compound (II), an acetyl group, a methoxymethyl group, a methoxyethoxymethyl group, a benzyl group or the like may be used. These protecting groups may be removed in suitable manners for their nature, in general, by acid hydrolysis.
The subsequent alkylation reaction may use an inert solvent appropriately selected from dimethylformamide, tetrahydrofuran, dioxane, acetone, acetonitrile and the like. A base that can be used in the alkylation reaction includes inorganic bases such as sodium hydride and potassium carbonate, as well as organic bases such as triethylamine and diisopropylethylamine. The reaction is generally carried out at room temperature to about 60xc2x0 C. Following the reaction, the product of interest may be isolated in a general manner.
In addition, when the product of interest has a substituted or unsubstituted amino group as group R1, such a compound may be prepared by amidating the product of interest, in which R1 is a hydroxyl group or a C1-6-alkoxy group, using amines corresponding to R1, such as methylamine, picolylamine, hydroxylamine and morpholine.
Method (3) Where R6 is a Cyano or C1-6-alkoxy-carbonyl Group, Y is an Oxygen Atom, and R5 is a Hydrogen Atom in Formula (I):
Compound (I) may be prepared by reacting a benzaldehyde derivative of formula (VIII):
R1xe2x80x94C(xe2x95x90X)xe2x80x94(CH2)mxe2x80x94C(R2)(R3)xe2x80x94Wxe2x80x94Arxe2x80x94CHOxe2x80x83xe2x80x83(VIII)
wherein
Ar, R1, R2, R3, m and W are as defined above;
with an active methylene compound of formula (IX):
R6xe2x80x94CH2xe2x80x94COxe2x80x94NR4xe2x80x94(CH2)nxe2x80x94Pyxe2x80x83xe2x80x83(IX)
wherein
R6 is a cyano or C1-6-alkoxy-carbonyl group; and
Py, R4 and n are as defined above;
through Knoevenagel condensation in the presence of a base catalyst.
Benzaldehyde derivative (VIII) and active methylene compound (IX), which are used as starting materials, are commercially available or may be prepared in a general manner.
This reaction may use an appropriate inert solvent, including organic solvents such as benzene, toluene and ethanol. A base catalyst that can be used in the reaction includes pyridine and piperidine. The reaction may be carried out at 80xc2x0 C. to 140xc2x0 C. Following the reaction, the product of interest may be isolated in a general manner.
Method (4) Where Y is a Sulfur Atom in Formula (I):
The compound of interest may be prepared by reacting the compound obtained from the above methods (1) to (3), i.e., an amide derivative in which Y is an oxygen atom in formula (I), with a sulfurizing agent such as Lawesson reagent for conversion into a thione derivative. This reaction may be carried out in an inert solvent, including toluene and xylene, in general, at 110xc2x0 C. to 140xc2x0 C. Following the reaction, the product of interest may be isolated in a general manner.
The product may be purified by any procedure commonly used, including column chromatography on silica gel or the like and recrystallization from ethyl acetate, acetone, hexane, methanol, ethanol, chloroform, dimethyl sulfoxide, water or the like. Examples of elution solvents for column chromatography include chloroform, methanol, acetone, hexane, dichloromethane, ethyl acetate, and combinations thereof.
The compound of formula (I) and pharmaceutically acceptable salt thereof (hereinafter, designated xe2x80x9ccinnamamide derivative (I)xe2x80x9d) have inhibitory activities against IL-6, IL-10 and IL-12 production and/or thromboxane A2 synthase. Such a compound may be an effective therapeutic agent for autoimmune diseases (e.g., nephrotic syndrome, immunological rejection in transplantation, rheumatism, allergy), circulatory disorders (e.g., ischemic heart disease, thromboembolic disorder, disorder of cerebral circulation), respiratory diseases (e.g., asthma), diabetes, liver disorders, tumors and the like. In particular, it may be an effective prophylactic or therapeutic agent for nephrotic syndrome.
Cinnamamide derivative (I) will be described with respect to a dose for administration and the formulation.
Cinnamamide derivative (I) can be administered to an animal and a human with or without a conventional pharmaceutical carrier. It may be formulated into any suitable pharmaceutical form as needed, including, but not limited to, oral formulations such as tablets, capsules, granules, fine granules and powders, as well as parenteral formulations such as injections and suppositories.
A daily dose of the oral formulation may vary depending on the age, weight and disease condition of a patient. In order to achieve an expected effect as an oral formulation, however, a suitable daily dose for an adult may generally be 1 mg to 2 g, based on the weight of cinnamamide derivative (I), which may be administered at several times per day.
The oral formulation may be prepared in a general manner using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch and/or inorganic salts.
In addition to these excipients, such a formulation may optionally contain binders, disintegrators, surfactants, lubricants, enhancers for the fluidity, flavoring agents, colorants, perfumes and the like. Specific examples for each ingredient will be presented below:
Binders: starch, dextrin, powdered acacia, gelatin, hydroxypropyl starch, methylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and Macrogol;
Disintegrators: starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted hydroxypropylcellulose;
Surfactants: sodium lauryl sulfate, soybean lecithin, sucrose esters of fatty acid, and Polysorbate 80;
Lubricants: talc, waxes, hydrogenated vegetable oils, sucrose esters of fatty acid, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol; and
Enhancers for the fluidity: light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
In addition, cinnamamide derivative (I) may be administered in suspension, emulsion, syrup or elixir, which may further contain corrigents and/or colorants.
A daily dose of the parenteral formulation may vary depending on the age, weight and disease condition of a patient. In order to achieve an expected effect as a parenteral formulation, however, a suitable daily dose for an adult may generally be 0.01 mg to 600 mg, based on the weight of cinnamamide derivative (I), which may be administered by intravenous injection, intravenous drip infusion, subcutaneous injection or intramuscular injection. Such a parenteral formulation may be prepared in a general manner using as a diluent distilled water for injection, physiological saline, aqueous glucose solution, vegetable oils for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like. The formulation may further contain disinfectants, antiseptics and/or stabilizers, if necessary. In view of the stability, the parenteral formulation may also be prepared by the following steps: freezing in a vial etc., standard lyophillization to remove water, followed by reconstitution of a liquid from the lyophilized product immediately before use. Further, the parenteral formulation may also contain optional additives such as isotonicities, stabilizers, antiseptics and/or soothing agents, if necessary.
Other parenteral formulations may be paints, such as external liquid preparations and ointments, and suppositories for intrarectal administration, which may be prepared in a general manner.
This specification includes part or all of the contents as disclosed in the specification of Japanese Patent Application No. 11-4384, which is a priority document of the present application.